In the year 2013-2014, we continued to focus on three major research area: 1) screening and characterizing drugs for combination therapy and transmission blocking; 2) studying molecular mechanisms of malaria pathogenesis using Plasmodium yoelii/mouse model; 3) molecular basis of an oocyst development defect. In collaboration with scientists in NCATS, we have completed a large-scale screening of drug combinations. Promising drug combinations were identified, and the data have been submitted for publication. We are also evaluating the effect of Ca++ and Na+ channel blockers on parasite response to artemisinin. Using rodent malaria parasite P. yoelii, we have made good progresses in studying parasite-host interaction in several directions: 1) We continued to map and evaluate candidate genes in the loci linked to host cytokine/chemokine response, leading to a publication in Gene and Immunity (Pattaradilokrat Genes Immun. 2014; 15: 145-152). We are currently testing parasites with amino acid substitutions in candidate genes and their association to cytokine levels and disease phenotypes. 2) We showed that type I interferon (IFN-I) played an important role in controlling parasitemia of rodent malaria parasite Plasmodium yoelii nigeriensis N67 infection; the results were published recently (Wu et al., PNAS. 2014; 111:E511-20). Now we are focusing on another disease phenotype---tissue necrosis after infection with another parasite. 3) We developed and tested a microarray platform for genotyping P. yoelii genome, leading to a publication recently (Nair et al, Mol Biochem Parasitol 2014; 194: 9-15). This genotyping platform is being used to type DNA samples from progeny of genetic crosses. 4) We linked an oocyst development defect to a locus on chromosome 6 of P. yoelii in our last report. We have knocked out the candidate gene and demonstrated the gene indeed plays a critical role in oocyst development. 5) Last year, we performed a genome-wide linkage analysis on host response to infection of progeny from a genetic cross and identified hundreds of parasite genetic loci linked to responses of many host genes. We have started testing some selected genes using genetic knockout and other methods. 6) We performed several additional crosses of P. y. negeriensis N67C and P. y. yoelii YM and have obtained 52 progeny. After characterizing the genotypes and phenotypes of the progeny, we identified some candidate genes. We are testing a primary candidate using genetic transformation of the parasites. 7) We have also crossed P. berghei ANNA and P. berghei NK165 and obtained several progeny to identify genes linked to cerebral malaria. We are sequencing the genomes of these progeny to identify polymorphisms for additional genetic markers, some of which could be the causative mutations. 8) Finally, we are also studying the molecular mechanism of apoptosis and necroptosis after P. yoelii infection. Some candidate host genes are being evaluated. Understanding the molecular mechanism of host-parasite interaction will allow development of effective measures for controlling parasite development and the disease it causes.